Hyperforin is considered to be the constituent of St. John's Wort responsible for its antidepressant activity (see, e.g., Chatterjee et al., Life Sci. (1998) 63:499-510). Hyperforin is the only known selective agonist of TRPC6 (canonical transient receptor potential) ion channel leading to influx of Ca+2 and Na+ ions into neurons and neuronal axonal sprouting (see, e.g., Leuner et al., FASEB J. (2007) 21:4101-4111). Unlike synthetic SSRI antidepressants, hyperforin causes an increase in synaptic serotonin and norepinephrine levels, possibly by antagonizing TRPC6. Therefore, TRPC6 may be a novel antidepressant target. Since there are few small molecules that are known to selectively activate TRPC channel proteins, and these proteins are being recognized as critical players in various aspects of human physiology, hyperforin is an important lead for discovery of new TRPC channel modulators and possibly new therapeutics (see, e.g., Ramsey et al., Annu. Rev. Physiol. (2006) 68:619-647). However, major drawbacks of hyperforin as a therapeutic lead are that it has poor water solubility and it is a potent activator of PXR (pregnane X receptor), which causes upregulation of CYPs (CYP3As and CYP2Cs) and the resultant metabolism of other drugs (see, e.g., Moore et al., Proc. Natl. Acad. Sci. USA (2000) 97:7500-7502). Hyperforin has also been reported to have beneficial effects in atopic dermatitis and psoriasis models (see, Leuner et al., J. Biol. Chem. (2008) 283:33942-33954, and Leuner et al., PLoS ONE (2011) 6:e14716). In addition, it protects pancreatic beta-cells from cytokine-induced apoptosis and therefore may be a treatment for Type I and Type II diabetes (see, Masiello et al., Int. J. Biochem. Cell Biol. (2008) 40:1509-1521). Agonists of TRPC6 may also be useful for treatment of asthma and chronic obstructive pulmonary disease (COPD) (see, e.g., Garbisa et al., J. Pharmacol. Exp. Ther. (2007) 321:492-500), kidney disorders (e.g., focal and segmented glomerulosclerosis: see, e.g., Winn et al., Science (2005) 308:1801-1804); and ischemic brain damage (see, e.g., Du et al., J. Clin. Invest. (2010) 120:3480-3492).

Hyperforin is a bicyclic polyprenylated acylphloroglucinol derivative and exists as a mixture of tautomers. The broad shape of most of hyperforins' 1H-NMR signals and the poor resolution of the 13C-NMR is characteristic of the tautomeric equilibrium (see, e.g., Beerhues, Phytochemistry (2006) 67:2201-2207). As a result of its important biological and medicinal properties and its unique complex structure, hyperforin has generated intense interest from the synthetic organic and scientific community (see, e.g., Barabé et al., Org. Lett. (2009) 11:4236-4238; Couladourous et al., Org. Lett. (2009) 11:4430-4433; Kraus et al., Tetrahedron Lett. (2003) 44:659-661; Mehta et al., Tetrahedron Lett. (2008) 49:1417-1420; Abe et al., Tetrahedron Lett. (2006) 47:6347-6351; Nicolaou et al., Angew. Chem. Int. Ed. (2005) 44:3895-3899; Spessard et al., Org. Lett. (2002) 4:1943-1946). To date only a single total synthesis has been accomplished by Shibasaki and co-workers, in 51 steps and 0.05% overall yield (see, e.g., Shimizu et al., Angew. Chem. Int. Ed. (2010) 49:1103-1106; Shimizu et al., Tetrahedron (2010) 66:6569-6584). Several syntheses of less complex bicyclic polyprenylated acylphloroglucinols have been achieved, but as yet none of those approaches have been applied to the more complex hyperforin (see, e.g., Nuhant et al., Org. Lett. (2007) 9:287-289; Qi et al., J. Am. Chem. Soc. (2007) 129: 12682-12683; Rodeschini et al., Org. Lett. (2006) 8:5283-5285; Siegel and Danishefsky, J. Am. Chem. Soc. (2006) 128:1048-1049). The enantioselective synthesis of hyperforin by Shibasaki is a landmark achievement, but it is not easily amenable to the synthesis of hyperforin analogs. Thus, there remains a need for a practical synthesis of hyperforin that will provide access to a wide variety of hyperforin analogs for biological evaluation.